Useful pro-drug forms of theophylline

ABSTRACT

There is provided novel and useful pro-drug forms of theophylline having the formula: ##SPC1## 
     Wherein R represents a member selected from the group consisting of a straight or branched C 4  -C 20  alkyl group, a straight or branched C 4  -C 20  alkenyl group, a substituted phenyl group of a substituted or unsubstituted naphthyl group whose substituents are selected from the group consisting of a hydroxy group, a C 1  -C 4  alkyl group, a C 1  -C 4  alkoxy group, a C 1  -C 4  acyloxy group, and a halogen atom (Cl, Br, I), and a substituted or unsubstituted heteroaromatic group whose substituents are selected from the group consisting of a hydroxy group, a C 1  -C 4  alkyl group, a C 1  -C 4  alkoxy group, a C 1  -C 4  acyloxy group, and a halogen atom (Cl, Br, I), and wherein A represents a member selected from the group consisting of a --CO-- group, a --CO--(CH 2 ) n  --CO-- group, wherein n represents an integer of from 1 to 16, a --CO--CH=CH--CO-- group (cis or trans), a ##SPC2## 
     Group, and a ##SPC3## 
     Group. 
     The compounds of this invention are useful in the treatment of asthma in warm-blooded animals. Upon administration, the compounds of this invention slowly go into solution and subsequently cleave prior to and/or during the absorption process, releasing theophylline in a sustained manner at a non-toxic, therapeutic level; that is, without the large blood level variations normally observed when theophylline per se is administered.

BACKGROUND OF THE INVENTION

1. FIELD OF THE INVENTION

The present invention is directed to novel and useful derivatives oftheophylline, a known drug useful in the treatment of asthma. Moreparticularly, the present invention is directed to certain "pro-drug"forms of theophylline useful in the treatment of asthma in warm-bloodedanimals, e.g. humans.

For the purposes of this application, the term pro-drug denotes aderivative of a known and proven prior art compound (i.e., theophylline)which derivative, when administered to a warm-blooded animal, "cleaves"in such a manner as to release the proven drug form and permit the sameto attain a sustained therapeutic level for a longer period of time thanthat which could be attained if the proven drug form per se wasadministered. More specifically, because of the very low watersolubility and low dissolution rate of the pro-drug forms of thisinvention, such forms enable theophylline to be released quite slowlythus permitting therapeutic blood levels of the same to be maintainedover an extended period of time, while at the same time, avoidingnon-toxic blood levels of theophylline to be reached. The pro-drug formsof this invention are cleaved so rapidly in aqueous solution that thepro-drug form per se does not reach the bloodstream, but rather,cleavage of the pro-drug occurs before and/or during the absorptionprocess. As such, substantial and sustained bioavailability is assured.

2. DESCRIPTION OF THE PRIOR ART

Theophylline, normally administered as the ethylenediamine salt(Aminophylline) or choline salt, is a useful and potent bronchodilatorcommonly prescribed for the treatment of bronchial asthma. Because it isreadily soluble, Aminophylline has for many years been accepted as aneffective bronchodilator when given orally. However, Aminophylline insolution becomes highly alkaline and is hydrolized by the gastric juicewith resultant gastric irritation from the free theophylline liberated.

5 to 12 mcg./ml of whole blood or 10 to 25 mcg./ml of plasma are therelative blood levels of theophylline generally accepted as necessary toachieve effective bronchodilation. See, E. G. Truitt, V. A. McKusick, J.C. Krantz, Jr; Pharm. Exp. Ther., 100, 309 (1950) and M. Warwick Turner;Brit. Med. Jr., 2, 67 (1957), respectively. These theophylline bloodlevels are, however, difficult to attain, since as a result of thegastrointestinal upset experienced, patients cannot tolerate an adequatetherapeutic dose of the drug. Reports in the literature with a varietyof theophylline derivatives have often shown not only that theophyllineblood levels achieved are below the values required for the relief of abronchospasm, but also that even when these therapeutic levels areobtained, they fall off extremely rapidly in the first few hoursfollowing administration of the drug. Thus, repeated dosing of thepatient abot every 3 to 4 hours is necessary. See, E. G. Truitt, V. A.McKusick, J. C. Krantz, Jr., and M. Turner-Warwick, and R. H. Jackson,J. I. McHenry, S. B. Moreland, W. J. Raymer, and R. L. Etter; Dis.Chest., 45, 75 (1964), and J. Schluger, J. T. McGuinn, and D. J.Hennesey; Amer. J. Med. Sci.: 233, 296 (1957), respectively.

In addition, even when therapeutic blood levels of theophylline areachieved, the amount of theophylline administered to a patient is soexcessive that the therapeutic blood level achieved approaches and oftenreaches toxicity.

In one attempt to overcome the above disadvantages associated withadministering theophylline, certain individuals have prepared acontinuous-release formulation, such that the release rate oftheophylline is dependent upon the formulation medium into which it isincorporated. That is, sustained therapeutic blood levels oftheophylline are achieved through the use of a particular pharmaceuticalformulation rather than chemical modification of the theophyllinemolecule. See, C. Boroda, R. B. Miller, S. T. Leslie, E. G. Nicol and I.Thompson; Clin. Pharm., 383 (1973) and D. McIntosh, Brit. J. Clin.Pharm., 12, 233 (1971) respectively.

Some theophylline derivatives, analogous to the compounds of formula (I)described hereinabove, have been prepared and described in theliterature for the purpose of studying their chemistry per se, withoutany indication of any pharmaceutical utility. For instance,7-acetyltheophylline was reported in three different articles. See, forinstance, T. Higuchi, H. K. Lee and Ian H. Pittman; Farm. Aikak., 80, 55(1971) and Y. Ishido, A. Hosono, S. Isome, A. Maruyama, and T. Sato;Bull. Chem. Soc. Japan, 37, 1389 (1964), respectively.

7-acetyltheophylline and 7-benzoyltheophylline were reported in H.Biltz, and K. Struffe, Ann., 404, 170 (1914) as well.

7-propionyltheophylline and 7-butyryltheophylline have also beenreported in the literature. See, Y. Ishido, A. Hosono, S. Isome, A.Maruyama, and T. Sato, supra.

Finally, U.S. Pat. No. 2,729,643 discloses certain7-carboxamidotheophylline derivatives useful as diuretics.

As for the compounds of formula (II) described herein above, no priorart of structural chemical or pharmacological significance is known.

SUMMARY OF THE INVENTION

It is one object of the present invention to provide novel and usefulpro-drug forms of theophylline, useful in the treatment of bronchialasthma in warm-blooded animals, e.g. humans.

It is another object of the present invention to provide novel anduseful pro-drug forms of theophylline which cleave in such a manner asto enable the original proven drug form (theophylline) to be releasedwhen administered to a warm-blooded animal at a slow, but continual,non-toxic therapeutic level and to further permit the cleaved moiety(ies) unassociated with the proven drug form to be excreted withoutabsorption or metabolized in a non-toxic fashion.

Still, it is another object of the present invention to provide noveland useful pro-drug forms of theophylline which because of their abilityto cleave before and/or during the absorption process insure thatsubstantial and sustained theophylline bioavailability as set forthabove is attained.

Accordingly, all of the above objects are satisfied when employing apro-drug of theophylline, having the formulae I and II set out below:##SPC4##

wherein R represents a member selected from the group consisting of astraight or branched C₄ -C₂₀ alkyl group, a straight or branched C₄ -C₂₀alkenyl group, a substituted phenyl group or a substituted orunsubstituted naphthyl group whose substituents are selected from thegroup consisting of a hydroxy group, a C₁ -C₄ alkyl group, a C₁ -C₄alkoxy group, a C₁ -C₄ acyloxy group, and a halogen atom (Cl, Br, I),and a substituted or unsubstituted heteroaromatic group whosesubstituents are selected from the group consisting of a hydroxy group,a C₁ -C₄ alkyl group, a C₁ -C₄ alkoxy group, a C₁ -C₄ acyloxy group, anda halogen atom (Cl, Br, I), and wherein A represents a member selectedfrom the group consisting of a --CO--group, a --CO--(CH₂)_(n) --CO--group, wherein n represents an integer of from 1 to 16, a--CO--CH=CH--CO-- group (cis or trans), a ##SPC5##

group, and a ##SPC6##

group.

In regard to the above generic formulae, the following remarks arepertinent from the standpoint of certain preferred embodiments relativeto the substituents "R" and "A." When R represents an alkyl group(straight or branched) of from 4 to 20 carbon atoms, the odd numberedalkyl groups beginning with C₇ are preferred; when R represents analkenyl group (straight or branched) of from 4 to 20 carbon atoms, theoleyl group is preferred; when R represents a substituted phenyl group,substitutents in the 4-position with an alkoxy group of from 1 to 4carbon atoms, or a 2-hydroxyphenyl group, or a 2-acyloxyphenyl of from 1to 4 carbon atoms are preferred; and when R represents a heteroaromaticgroup, a 2-, 3-, or 4-pyridyl group or any equivalent analog thereof,such as a quinoline group is preferred.

With respect to substituent A, when this substituent represents a--CO--(CH₂)_(n) --CO-- group, wherein n represents an integer of from 1to 16, the integer of from 1 to 4 is preferred; and when A represents a--CO--CH=CH--CO-- group (cis or trans), the trans form is preferred.

As indicated earlier, all the compounds within the present inventionsatisfy the objectives noted above; however, certain compounds arepreferred as set forth below;

1. 7-hexanoyltheophylline

2. 7-octanoyltheophylline

3. 7-decanoyltheophylline

4. 7-dodecanoyltheophylline

5. 7-myristyltheophylline

6. 7-palmityltheophylline

7. 7-stearyltheophylline

8. 7-[2-hydroxy]-benzoyltheophylline

9. 7-[2-acetyloxy]-benzoyltheophylline

10. 7,7'-carbonylditheophylline

11. 7,7'-succinylditheophylline

12. 7,7'-terephthaloylditheophylline

13. 7,7'-fumaroylditheophylline

14. 7,7'-glutarylditheophylline

15. 7,7'-adipylditheophylline

DETAILED DESCRIPTION OF THE INVENTION

Preparation of the compounds of formula (i):

using stoichiometric amounts of each reactant, the compounds encompassedwithin Formula (I) can be prepared by any one of methods "A" through "C"described below

A. Theophylline can be reacted with the appropriate corresponding acidanhydride wherein R is defined as above. The reaction is carried out inthe presence of an inert organic solvent, such as benzene, toluene, achlorinated hydrocarbon, e.g., 1,2-dichloroethane, dichloromethane,chloroform, or the like. The reaction is carried out at a temperatureranging from room temperature to 120° C (preferably, however, at theboiling point of a solvent employed), standard pressure and over aperiod of time ranging from 2 to 6 hours.

B. In one alternative procedure, theophylline can be reacted with theappropriate corresponding acyl halide (Cl, Br, I), wherein R is definedas above, in the presence of a suitable organic or inorganic base and inthe presence of a suitable inert organic solvent. Illustrative organicor inorganic bases suitable for this reaction are pyridine,triethylamine, K₂ CO₃, Na₂ CO₃, etc. Illustrative inert organic solventssuitable for this reaction are benzene, toluene, xylene, and chlorinatedhydrocarbons as illustrated in procedure (A) above. The reaction isadvantageously carried out at a temperature range of from roomtemperature to 100° C (preferably at the boiling point of the solventemployed), standard pressure and over a reaction period of from 2 to 6hours.

C. Alkali or alkaline earth metal salts of theophylline (Na, K, Li, Ca,Mg, etc.) or the thallous [Tl(1)]salt of theophylline can be reactedwith the appropriate corresponding acyl halide as defined in procedure(B) above. The reaction is carried out in the presence of an inertorganic solvent, such as ether, dioxane, tetrahydrofuran,1,2-dimethoxyethane, etc. The reaction is advantageously carried out atroom temperature, standard pressure, and for a period of time rangingfrom 2 to 6 hours.

Employing any one of the above procedures (A) through (C) above, thecrude material obtained therefrom can be purified by way ofrecrystallization from an inert anhydrous organic solvent or mixtures ofsame, e.g., hydrocarbon solvent such as hexane, heptane, petroleumether, ligroin, etc., or an admixture of any of the above solvents witha chlorinated hydrocarbon solvent such as 1,2-dichloroethane,dichloromethane, etc.

Preparation of the compounds of formula (ii):

these compounds are prepared using procedures (A) or (B) listed above,with the exception that the appropriate acyl halide is substituted withthe dihalide of the appropriate corresponding dicarboxylic acid.

Advantageously, in dealing with those dihalides which undergo sidereactions, such as succinyl dihalide, fumaryl dihalide and the like, thetemperature of the reaction will range from -78° C to room temperature.The pressure remains standard and the reaction time will beapproximately 12 hours.

With respect to those dihalides which do not undergo side reactions, thereaction temperature will range from room temeprature to 120° C, thepressure will remain standard and the reaction time will vary from 2 to6 hours.

It should be emphasized that because of the nature of the reactionsrequired to prepare compounds falling within formulae (I) and (II), itwill be necessary to maintain strict anhydrous conditions throughout thesynthesis. In addition, because of the stability problems incurred instoring such compounds following preparation, anhydrous storageconditions are also required.Without further elaboration, it is believedthat one of ordinary skill in the art can, using the proceedingdescription, utilize the present invention to its fullest extent. Thefollowing specific embodiments are, therefore, to be construed as merelyillustrative, and not limitative of the remainder of the specificationand claims in any way whatsoever.

EXAMPLE I SYNTHESIS OF ILLUSTRATIVE THEOPHYLLINE DERIVATIVES

1. 7-octanoyltheophylline - 4.5 g (0.025 M) of theophylline was added to200 ml of anhydrous 1,2-dichloroethane containing 5 ml (0.062 M) ofpyridine. 4.86 g (0.013 M) of octanoyl chloride, diluted with 50 ml of1,2-dichloroethane was then added to the solution. The mixture washeated under reflux for 2 hours and then cooled to 0° C. The precipitateformed was filtered and the filtrate was evaporated to dryness under arotoevaporator. The crystals were recrystallized from heptane to give anessentially quantitative yield of the final compound, MP 62°-63° C.Anal. Calcd. for C₁₅ H₂₂ N₄ O₃ : C, 58.81; H, 7.28; N, 18.28. Found: C,58.68; H, 7.24, N, 18.48.

2. Essentially quantitative yields of all the remaining theophyllinederivatives of Formula (I) can be prepared by following the reactionscheme described in paragraph (1) above by simply substituting theappropriate acyl chloride ##EQU1## wherein R is as defined above. Thefollowing specific derivatives have been prepared in this manner:

A. 7-pivaloyltheophylline

B. 7-hexanoyltheophylline

C. 7-decanoyltheophylline

D. 7-oleoyltheophylline

E. 7-palmitoyltheophylline

F. 7-myristyltheophylline

G. 7-stearyltheophylline

H. 7-[2-hydroxy]-benzoyltheophylline

I. 7-[2-acetyloxy]-benzoyltheophylline

3. 7,7'-succinylditheophylline - 9 g (0.05 M) of grounded theophyllinewas suspended in about 1 liter of anhydrous CHCl₃. The mixture wascooled to -20° to 40° C (dry ice - 1,2-dichloroethane bath). 3.8 g(0.0247 M) of succinyl chloride was diluted with 50 ml of anhydrousCHCl₃ and this solution was then added to the initial solution. 5 ml(0.062 M) of pyridine, diluted in 50 ml of CHCl₃ was then added dropwiseto the resulting solution. The solution was then stirred and maintainedat a temperature of -20° to 40° C for a period of from 4 to 6 hours togive a white crystalline final product in essentially quantitativeyield. The final product was then filtered and washed with anydrousCHCl₃ (3 × 300 ml) to give an essentially quantitative yield of thefinal product, MP 266° C. Anal. Calcd for C₁₈ H₁₈ N₈ O₆ : C, 48.87; H,4.10; N, 25.33. Found: C, 48.44; H, 4.19; N, 25.77.

4. By substituting the appropriate acyl chloride ##EQU2## in thereaction scheme described in paragraph (3) above, wherein A is definedas above, the remaining 7,7'-ditheophylline derivatives of Formula (II)can be prepared in essentially quantitative yield. Illustrativecompounds prepared in an analogous manner are:

A. 7,7'-glutarylditheophylline

B. 7,7'-terephthaloylditheophylline

C. 7,7'-carbonylditheophylline

D. 7,7'-fumaroylditheophylline

In each of the above Examples I(1) - I(4), reference to "essentiallyquantitative" with respect to the yield of each final product denotes atleast a 90-95% yield.

EXAMPLE II DISSOLUTION RATE - THEOPHYLLINE v. THEOPHYLLINE DERIVATIVESOF THIS INVENTION

In FIG. 1 attached hereto, there is provided a plot of the dissolutionrates for theophylline versus selected theophylline derivatives of thepresent application. As compared to theophylline, the theophyllinederivatives of the present application are much less soluble, thuspermitting theophylline to be released in a controlled, non-toxictherapeutic amount over an extended period of time. On the other hand,with theophylline, the dissolution rate is so rapid that a non-toxicsustained therapeutic release cannot be achieved.

The dissolution studies were conducted directly in accordance with theguidelines set forth in the U.S. Pharmacopeia XVIII (U.S.P.) at pages934-935. The apparatus and materials employed were within U.S.P.requirements.

The dissolution rate of the drugs were run in 500 ml of distilled watercontaining two drops of Tween 80 in a standard dissolution pot at atemperature of 25° C (+ or - 0.5° C) via a constant temperature waterbath. Samples of 100 to 200 mesh powder of each compound tested weretransferred directly into the dissolution medium and stirred with astandard U.S.P. stainless steel paddle. The paddle was placed at thecenter of the 500 ml dissolution medium and rotated at a rate of 100rpm. After a constant reading was obtained, the solution was sonicatedfor 15 minutes to obtain the infinite reading. All samples were run atleast twice. The concentration of each sample in the dissolution mediumnever exceeded 5% of the solubility of theophylline.

EXAMPLE III IN VIVO COMPARISON OF THEOPHYLLINE v.7,7'-SUCCINYLDITHEOPHYLLINE

In order to determine the superiority of the theophylline derivatives ofthis invention over theophylline per se, the following in vivo study wascarried out.

Beagle dogs of both sexes, weighing 10 to 15 Kg. were fasted for 12hours prior to use. Theophylline (30 mg./kg.) and7,7'-succinylditheophylline (equivalent to 30 mg./Kg. of theophylline)were suspended in 5% methylcellulose and administered orally via aconventional gastric delivery tube. Each suspended drug solution waspepared immediately prior to administration. 10 ml of blood waswithdrawn from each dog immediately prior to drug administration. Then,blood samples consisting of 10 ml of blood were obtained at 15, 30, 60,120, 240, 360, 480 and 720 minutes after drug administration. The plasmawas separated conventionally and stored in a freezer pending assay.Theophylline concentrations in plasma were determined by thespectraphotometric method of Shack and Waxler*. 2 ml of plasma wasacidified with 1 N HCl to a pH of 5.5-6 and then was extracted with 20ml of organic phase, 5% isopropanol in chloroform. The organic phase wasre-extracted with 3 ml of 1 N sodium hydroxide. The absorbance wasdetermined with a 1 cm pathlength cell in a UV spectrophotometer (Carey14).

A plot of the results of this study is set forth in FIG. 2 attached. Theresults clearly establish the superiority of the pro-drug forms of thisinvention over theophylline from a non-toxic, sustained and controlledtherapeutic release standpoint.

The results of the above study further demonstrate that thepro-theophylline derivatives of this invention can be tolerated even inhigher doses other than that administered (30 mg/Kg.) in comparison totheophylline per se without compromising the recited objectives of theinvention.

When the remaining compounds of the present invention are subjected toin vivo testing as above, suitable sustained therapeutic levels oftheophylline, within the intent and purpose of this invention will beobtained.

The pro-drug forms of this invention are suitably administered in oraldosage form, such as tablet or capsule, by combining the same in atherapeutic amount with any oral pharmaceutically acceptable inertcarrier, such as lactose, starch (pharmaceutical grade), dicalciumphosphate, calcium sulfate, Kaolin, Mannitol, and powdered sugar. Inaddition, when required, suitable binders, lubricants, disintegratingagents, and coloring agents can also be added. Typical binders includestarch, gelatin, sugars, such as sucrose, molasses, and lactose, naturaland synthetic gums such as acacia, sodium alginate, extract of Irishmoss, carboxymethylcellulose, methycellulose, and polyvinylpyrrolidone,polyethylene glycol, ethylcellulose and waxes. Typical lubricants foruse in these dosage forms can include, without limitation, boric acid,sodium benzoate, sodium acetate, sodium chloride, leucine, andpolyethylene glycol. Suitable disintegrators can include, withoutlimitation, starch, methylcellulose, agar, bentonite, cellulose and woodproducts, alginic acid, guar gum, citris pulp, carboxymethylcellulose,and sodium lauryl sulfate. If desired, a conventionally pharmaceuticallyacceptable dye can be incorporated into the dosage unit form, i.e., anyof the standard FD&C dyes.

Any skilled artisan can prepare these oral dosage forms by simplyreferring to the oral dosage form preparatory procedure outlined inREMINGTON'S PHARMACEUTICAL SCIENCES, Fourteenth Edition (1970), pages1659 through 1698 inclusive.

While the therapeutic dosage range for the compounds of this inventionwill vary with the size and needs of the patient, generally speaking,therapeusis on a daily basis is achieved by administering 10 mg. per Kg.of body weight, about every 8 to 12 hours.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand/or modifications to the invention for adapting it to various usagesand conditions. As such, such changes and modifications are properly,equitably and intended to be, within the full range of equivalence ofthe following claims.

What we claim is:
 1. A pro-drug of theophylline having the formula##SPC7##wherein R represents a member selected from the group consistingof straight or branched C₄ -C₂₀ alkyl, straight or branched C₄ -C₂₀alkenyl, substituted phenyl or substituted or unsubstituted naphthylwhose substituents are selected from the group consisting of hydroxy, C₁-C₄ alkyl, C₁ -C₄ alkoxy, acyloxy derived from an alkanoic acid of up to4 carbon atoms chlorine, bromine, and iodine, and 2-,3-,4-pyridyl orquinoline and wherein A represents a member selected from the groupconsisting of --CO--, --CO--(CH₂)_(n) --CO-- wherein n represents aninteger of from 1 to 16, --CO--CH=CH-- CO-(cis or trans), ##SPC8## and##SPC9##
 2. The compound of claim 1 wherein R represents an odd numberedalkyl of from C-7 to C-20.
 3. The compound of claim 1 wherein Rrepresents oleyl.
 4. The compound of claim 1 wherein R represents phenylsubstituted in the 4-position with hydroxy or C₁ -C₄ alkoxy,2-hydroxyphenyl, or 2-acyloxyphenyl wherein the acyloxy is derived froman alkanoic acid of up to 4 carbon atoms.
 5. The compound of claim 1wherein A represents --CO--(CH₂)_(n) --CO-- in which n is an integer offrom 1-4.
 6. The compound of claim 1 wherein A represents trans--CO--CH=CH--CO--.
 7. The compound of claim 1: 7-hexanoyltheophylline.8. The compound of claim 1: 7-octanoyltheophylline.
 9. The compound ofclaim 1: 7-decanoyltheophylline.
 10. The compound of claim 1:7-dodecanoyltheophylline.
 11. The compound of claim 1:7-myristyltheophylline.
 12. The compound of claim 1:7-palmityltheophylline.
 13. The compound of claim 1:7-stearyltheophylline.
 14. The compound of claim 1:7-[2-hydroxy]-benzoyltheophylline.
 15. The compound of claim 1:7-[2-acetyloxy]-benzoyltheophylline.
 16. The compound of claim 1:7,7'-carbonylditheophylline.
 17. The compound of claim 1:7,7'-succinylditheophylline.
 18. . The compound of claim 1:7,7'-terephthaloylditheophylline.
 19. The compound of claim 1:7,7'-fumaroylditheophylline.
 20. The compound of claim 1:7,7'-glutarylditheophylline.
 21. The compound of claim 1:7,7'-adipyldilheophylline.